1. Field of the Invention
This invention relates to intravaginal drug delivery devices for the administration of an antimicrobial agent or a mixture thereof. Preferably, it relates to intravaginal drug delivery devices for the treatment or prevention of a disease condition exacerbated by a bacterial, fungal, viral, and/or protozoal infection in a human or other animal female. In particular, it relates to intravaginal drug delivery devices, such that, for example, the symptoms associated with a vaginal disease condition of, for example, bacterial, fungal, viral and/or protozoal origin may be alleviated. Alternatively, the invention relates to intravaginal drug delivery devices for the local treatment of a disease condition, preferably a vaginal disease condition. Most preferably, the invention relates to the intravaginal delivery of quinolones, macrolides, clindamycin, tetracyclines, antibacterial and antifungal imidazoles and antiviral agents such as acyclovir, for the treatment of vaginitis of bacterial, fungal, viral and/or protozoal origin in a human female.
2. Related Background Art
Vaginitis (microbial infection of the human vagina) is the most common gynaecological problem encountered in the human female within the primary healthcare setting. Vaginitis is predominantly due to infections of bacterial, fungal (including yeast), viral and/or protozoal origins.
Bacterial vaginosis (non-specific vaginitis) is the most common type of bacterial vaginitis in women (Petersen, C. S et al, Acta Dermato-Venereologica Vol. 79, pp. 414-415, 1999), representing about 40% of all vaginitis. Bacterial vaginosis is a polymicrobial, primarily anaerobic, infection and is associated with a reduction in Lactobacillus species, together with a massive overgrowth in anaerobic micro-organisms, notably Gardnerella vaginalis and Chlamydia trachomatis and certain Prevotella and Mobiluncus species. Opportunistic species such as Staphylococcus epidermidis and Enterococcus faecalis may also appear.
Trichomonas vaginalis is a single-celled protozoal parasite of the human vagina. It is the organism responsible for trichomoniasis, a further aspect of the collective condition referred to as vaginitis. Approximately one in five human females will develop trichomoniasis at some point during their reproductive years.
Metronidazole has long been taken by the oral route for these conditions but orally administered metronidazole is associated with a range of unpleasant side effects, i.e. nausea and vomiting, gastrointestinal disturbances, headache, peripheral neuropathy, in addition to a disulfiram-like reaction in the presence of alcohol (British National Formulary 2000). Local intravaginal administration of an antimicrobial agent such as metronidazole might be expected to avoid most of these unwanted side effects.
Intravaginal drug delivery systems generally fall into two main groups, those adapted from semi-solid topical systems (usually applied using a vaginal applicator device) and those designed specifically for intravaginal use. The former, which are semi-solids, include semi-solid ointments, creams and gels. U.S. Pat. No. 5,840,744 describes an intravaginal preparation of the former group in the form of a non-flowing gel containing 375 mg or less of metronidazole dispersed in a polyacrylic acid polymer. An intravaginal semi-solid preparation of metronidazole is also commercially available as METROGEL-VAGINAL (Trade Mark), containing 0.75 g % by weight of the drug. The recommended dose for the treatment of bacterial vaginosis is 37.5 mg once or twice daily, applied for a five day period using an intravaginal applicator containing, for each dose, approximately 5 g of gel. This yields a total dose of 187.5 mg or 375 mg metronidazole over the 5 day treatment period.
Other examples of semi-solid topical systems for vaginal application include CANESTAN (Trade Mark) cream, containing 1% Clotrimazole with a suggested daily dose of about 500 mg; CLEOCIN/DALACIN (Trade Marks) cream, containing 2% Clindamycin (as phosphate) with a suggested daily dose of 100 mg; ECOSTATIN or PEVARYL (Trade Marks) creams containing 1% Econazole Nitrate; GYNO-DAKTARIN (Trade Mark) cream containing 2% Miconazole Nitrate; SULTRIN (Trade Mark) cream containing 3.4% Sulphathiazole, 2.8% Sulphacetamide and 3.7% Sulphabenzamide; NIZORAL (Trade Mark) cream containing 2% Ketoconazole with a suggested daily dose of about 100 mg; and TERAZOLE (Trade Mark) cream containing 0.8% Terconazole with a suggested daily dose of 40 mg.
Intravaginal administration of antimicrobial agents such as metronidazole, clindamycin, clotrimazole and econazole in the form of such a semi-solid topical preparation, although offering advantages over the oral route in respect of avoiding some unwanted side effects, nevertheless suffers from several disadvantages.
These are:                Patient compliance is problematic, since such intravaginal gel preparations currently require once or twice daily applications over a 5 day period using specially designed applicators. Additionally, it is not possible for the patient to immediately terminate the treatment at any time by removal of the semi-solid topical preparation, in the event of any adverse reaction being noted.        Messiness during application of such a semi-solid preparation. In addition, given the volume of material to be delivered intravaginally and their rheological characteristics, semi-solid preparations will leak from the vaginal space following administration so that the available concentration of active agent in solution within the vaginal space will be non-optimal and non-constant for a prolonged period of time.        Where resistant isolates arise, a higher drug loading is needed since the minimum inhibitory concentration of the drug which, for metronidazole, for example, is greater than the 128 μg per ml in solution of normal drug-sensitive isolates.        
Many of the problems associated with intravaginal delivery of metronidazole and other antimicrobial agents for the treatment or prevention of a susceptible disease condition such as bacterial vaginosis or the like could be overcome by the use of an intravaginal drug delivery device, not selected from those adapted from semi-solid topical systems but, rather, selected from those designed specifically for intravaginal use. The latter, being systems designed for intravaginal use, include tablets, pessaries, rod-shapes, ring-shapes and films for adhesion to the mucosal epithelium. While these latter systems can be based on compressed powders, hydrogels, waxes or elastomers, the present invention concerns itself solely with those latter systems formed from elastomers.
Known pessary-type systems for vaginal application include BETADINE (Trade Mark) pessaries for twice-daily administration; GYNO-DAKTARIN 1 (Trade Mark) vaginal ovules for single dose administration; GYNO-DAKTARIN 1 (Trade Mark) pessaries for once-daily administration; and GYNO-PEVARYL 1 (Trade Mark) pessaries for single dose administration. These known pessary-type systems, however, also suffer from poor patient compliance since they either must be repeatedly administered over a prolonged period of time or, if a single dose, do not deliver sufficient antimicrobial agent. Such pessary-type systems are not elastomeric systems.
Intravaginal elastomer drug delivery devices, designed to deliver steroidal sex hormones, are well known in the art. Jackanicz (Jackanicz, T. M., Vaginal Contraception: New Developments. Harper and Row, Hagerstown, pp. 201-212, 1979) teaches that three basic designs of intravaginal elastomer drug delivery device are possible, though additional design variations do exist. The three basic types are the homogeneous design, the shell design and the core design:                a) The homogeneous or “matrix” design, in which the active agent is homogeneously distributed in an elastomeric system. This design provides for an exponential (first order) release decay, characterised by an initial high release of drug, followed by a lower release rate of drug. This design cannot sustain a controlled, substantially constant drug release rate, which will be recognised by those skilled in the art as “zero order release”, over a prolonged period. Current teaching discourages the use of such “matrix” designs since a controlled substantially constant “zero order” drug release rate is now preferred.        b) The shell design, in which the active agent is contained in a narrow band between a non-medicated central elastomeric core and a narrow, outer non-medicated elastomeric sheath.        c) The core design, in which the active agent is homogeneously mixed with an elastomeric polymer to form a homogeneous core, the whole being surrounded by a rate controlling, non-medicated hydrophobic elastomeric sheath.        
Intravaginal elastomer drug delivery devices of the shell or core design are currently preferred for the delivery of steroidal sex hormones, in that they facilitate substantially constant (or zero order) oestrogen and/or progestogen release over a prolonged period of time.
There is no teaching in the scientific or patent literature that an intravaginal elastomeric drug delivery device may deliver a non-steroidal antimicrobial agent for treating or preventing a susceptible disease condition such as vaginitis of susceptible bacterial, fugal, viral and/or protozoal origins. This is despite intravaginal elastomeric drug delivery devices being known to those skilled in the art and the clinical benefits of intravaginal application of antimicrobial agents such as metronidazole, clindamycin, clotrimazole or econazole, albeit from a semi-solid topical system or a non-elastomeric solid delivery system, being similarly known for many years.
Many of the problems associated with treatment or prevention of a susceptible disease condition such as bacterial vaginosis or the like could be overcome by incorporating an antimicrobial agent in a suitable intravaginal elastomer drug delivery device of matrix design. Such a device would be capable of releasing the agent under first order release decay in an initially high “loading” rate, which is desired for an antimicrobial agent, followed by a lower “maintenance” rate over several days such that, in use, the fluid in the vaginal space contains the antimicrobial agent at a concentration above its minimum inhibitory concentration.